Clinical constructs and therapeutic discovery.

Schizophrenia, as a single disease entity, has been the major paradigm during the past 100 years. Classification has increasingly emphasized diagnostically discriminating psychotic symptoms. This has made reality distortion and thought disorder the defining qualities of the disorder. One result is 50 years of developing dopamine antagonist antipsychotic drugs while neglecting novel therapeutic pathways related to nonpsychotic pathology. The domains of psychopathology provides an alternative paradigm. In this paradigm, the relative independence of reality distortion, disorganization, negative pathology, and impairments in cognition is stressed. Application of this paradigm has revealed that impaired cognition and negative symptoms are robustly associated with poor functional outcomes. Antipsychotic drugs fail to address these pathologies. These unmet treatment needs are clinical targets for drug discovery involving novel therapeutic pathways.